PROJECT SUMMARY Viral infections have profound effects on human health. Acute viral infections cause damage to host tissues through cytopathic effects or via the inflammatory or immune responses they induce. Acute viral infections also predispose to secondary bacterial infections ? particularly pneumonias. Persistent or chronic viral infections that are associated with prolonged viral replication, such as Hepatitis B and C viruses (HBV, HCV) and human immunodeficiency virus (HIV), also cause altered and impaired immune responses against bacteria, cancer, vaccines, and other inflammatory stimuli. Type I IFNs are produced abundantly during viral infections and in response to viral products such as double-stranded RNA. These cytokines ligate a common ubiquitously- expressed receptor (IFNAR) to dramatically alter cellular physiology and elicit diverse effects on host inflammatory and immune responses. The ability of type I IFNs to induce expression of IFN stimulated genes (ISGs) with antiviral effector functions has thus long been known to promote cell-intrinsic host resistance during acute viral infections. However, these cytokines also have regulatory effects that are associated with increased susceptibility to many acute bacterial infections, as well as chronic viral infections and post-viral bacterial infections. The studies outlined in this proposal investigate the relative importance of myeloid cell IFNGR down regulation as a target of immune suppression by type I IFNs. The impact of this process will be analyzed using the recently generated fGR1 transgenic mouse model. The impact of fGR1 expression on macrophage IL-10 production and viral persistence will be investigated, as will its impact on neutrophil responses and secondary bacterial infections of the lung and bloodstream.